The Effects of Thermoneutral Housing on GSK3 activation and PGC‐1alpha Muscle Content After Voluntary Wheel Running in Mice

Background Glycogen synthase kinase‐3 (GSK‐3) is a serine/threonine protein kinase constitutively active at rest. GSK‐3 is known to regulate muscle glucose homeostasis and PGC‐1α expression. Studies have shown that acute and chronic muscle activation can inhibit GSK‐3 by promoting inhibitory serine9 phosphorylation; and this inhibition may mediate some of the beneficial effects of regular exercise including enhanced fatigue resistance. In light of recent evidence demonstrating the importance of housing mice at thermoneutrality to better mimic human metabolism and physiology, we investigated the protein levels of phosphorylated/total GSK3 and PGC‐1a in exercised and sedentary mice housed within their thermoneutral zone (TN, 29°C) or at room temperature (RT, 22°C). Methods Tricep muscles were obtained as part of another study conducted at the University of Guelph. Briefly, eight‐week old male mice (Charles River, QC, Canada) were purchased and acclimated to RT or TN for two weeks. Mice were then weight‐matched into sedentary (SED) or voluntary wheel running (VWR) groups, where mice had free access to a running wheel for up to 6 weeks. Following the intervention, mice were euthanized and tricep muscles were collected. Western blot analyses were done to examine protein levels of phosphorylated (Ser9) GSK3, total GSK3, and PGC‐1a. Pearson's correlational analyses were conducted to examine the associations between total GSK3 and PGC‐1a and phosphorylated:total GSK3 and PGC‐1a. Results Our results indicate that at RT GSK3 content was significantly reduced (‐38%) with VWR, which led to a 1.5‐fold increase in the Ser9 phosphorylated:total GSK3 ratio. This suggests that when housed at RT, VWR led to lower GSK3 activation. However, when housed at TN, these effects were not observed. When examining, PGC‐1α content, we found a significant elevation in both RT (2.3‐fold) and TN (3.5‐fold) VWR groups. Correlational analyses detected a negative association between total GSK3 content and PGC‐1α (r = ‐0.45, p = 0.03). Conversely, we found a positive association between phosphorylated:total GSK3 and PGC‐1α (r = 0.45, p = 0.04) suggesting that mice with greater phosphorylated GSK3, and thus lower activation, had greater levels of PGC‐1α. Conclusions Together our data suggests that VWR inhibits GSK3 in muscle when mice are housed at RT but not at TN. Though PGC‐1α was elevated in both VWR conditions, our correlational analyses reinforce the link between muscle GSK3 content/activation and PGC‐1α. In the future, it would be of interest to determine the impact of combined VWR and GSK3 inhibition in mice.

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